| Intersection of fibrin(olysis) and inflammation at the oral mucosa barrier Lakmali Silva. |
Abstract
Objectives: Herein, we focus on the role of fibrin, a proinflammatory molecule, excessive deposition of which can cause chronic inflammation and severe tissue damage via unknown mechanisms. Fibrin removal, fibrinolysis, is achieved by the proteolytic activity of plasmin. The critical role of defective fibrinolysis becomes evident in patients with the autosomal recessive disease: type I plasminogen (Plg) deficiency. Indeed, mucosal lesions in humans and mice with Plg deficiency are also characterized by excessive fibrin deposition. We hypothesized that insufficient plasmin-mediated fibrinolysis is a key contributor to mucosal immunopathology of periodontal disease.
Methods: We sought to understand the mechanistic link between mucosal fibrin deposition and immunopathology by using an array of genetically engineered mouse models, including Plg-/-, and Plg-/-Fgg390-396A (mutation in the aMb2 integrin binding site on the fibrin gamma-chain).
Results: We demonstrate that (i) Plg-deficient mice develop spontaneous and severe periodontal bone loss with persistent extravascular fibrin deposits compared with littermate controls, (ii) Plg-deficient mucosal lesions have a significantly increased neutrophil infiltration, (iii) abrogating the engagement of fibrin to neutrophils through the aMb2 leukocyte integrin receptor was sufficient to prevent Plg deficiency-associated periodontal bone loss, (iv) fibrin-aMb2-neutrophil engagement activated neutrophil effector functions, including the production of reactive oxygen species and neutrophil extracellular traps, and (v) removal of extracellular DNA by DNase I treatment and blocking NETosis via depletion of neutrophil elastase, controlled periodontitis in Plg-/- mice.
Conclusion: Our work uncovers fibrin as a critical regulator of neutrophil effector functions within the oral mucosal tissue microenvironment and suggests fibrin-neutrophil engagement as a pathogenic instigator and therapeutic target in oral mucosal disease, periodontitis.
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